DESCRIPTION (provided by principal investigator): Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the US with another 150,000 at risk. HD is characterized by motor, cognitive and psychiatric symptoms that often progress and result in the patient's death in about 10-20 years after disease onset. HD is caused by a polylgutamine repeat expansion in mutant Huntington, resulting in the relentless progression of neurodegeneration primarily targeting the striatal neurons but also affecting the cortical neurons. Currently, there is no treatment or cure for HD. Since mutant huntingtin (mhtt) is widely expressed in the brain and in the body but neuro degeneration in HD primarily targets the striatal and cortical neurons, a critical yet unanswered question in HD is how does the widely distributed mhtt cause such selective patterns of neuro degeneration? To address this question, we first will ask where mhtt expression is critical for disease pathogenesis. Using a novel series of HD mouse models that can express mhtt or its toxic fragments in different types of cells in the brain, we discovered that mhtt fragments can induce not only the intrinsic toxicities to the neurons in which it is expressed but also toxic interactions between different types of neurons. Furthermore, we found that switching off mhtt expression in the cortical neurons results in a significant but partial rescue of both the behavioral deficits and striatal toxicities in HD mice. These exciting findings underscore the need to study whether and how the cortical and striatal neurons may act together to elicit HD. We designed the following aims to address this critical question: Aim 1. Is mhtt expression in the striatum necessary for HD pathogenesis? Aim 2. Can switching off full length mhtt expression in both the cortex and striatum synergically reduce key disease phenotypes in HD mice? Aim 3. Can switching of full length mhtt only in the cortical pyramidal neurons and striatal medium spiny neurons be sufficient to induce key aspects of HD phenotypes in vivo? The completion of our study may reveal whether mhtt exert synergistic toxic effects from within two types of neurons (i.e. the striatal and cortical neurons) to elicit the major disease phenotypes in HD. Our study may support the molecular dissection of HD pathogenic mechanisms in these two cell types, and may further inform us on the optimal strategies of local delivery of mhtt reducing therapeutics (i.e. RNA interference, antisense oligonucleotides or intrabodies). PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the US and another 150,000 at risk. Currently, HD is not treatable or curable, and the patients invariably suffer from the motor, cognitive and psychiatric symptoms that often relentlessly progress toward an eventual bedridden state and death about 10-20 years after the disease onset. Our proposed study is aimed at identifying the critical neuronal cell types targeted by toxic mhtt to elicit the key disease phenotypes in HD. Hence, our study may provide the crucial cellular targets from which we can dissect the molecular pathogenic mechanisms and to deliver HD therapeutics.